Polyphenols in the Prevention and Treatment of Colorectal Cancer: A Systematic Review of Clinical Evidence
Abstract
:1. Introduction
2. Materials and Methods
2.1. Search Strategy and Selection Criteria
2.2. Inclusion and Exclusion Criteria
2.3. Data Extraction
2.4. Assessment of Risk Bias
3. Results
3.1. Article Selection
3.2. Data Extraction
3.2.1. Characteristics of the Selected Studies
3.2.2. Patients
3.3. Risk of Bias
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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---|---|---|---|---|---|---|---|---|---|
Flavopiridol (synthetic flavone) | Isolated compound 50 mg/m2/day via a 72 h continuous infusion every 14 days. | USA | 20 patients Advanced CRC unresectable adenocarcinoma of the colon or rectum | Both | 42–80 | Phase II trial of flavopiridol in previously untreated patients with advanced CRC | Examine flavopiridol as a chemotherapy modulating agent | No anticancer activity by itself | [24] |
Flavopiridol (synthetic flavone) | Isolated compound (40–90 mg/m) 2–3 h after irinotecan and before 5FU | USA | 31 with CRC, 43 other tumors. No control group Plasma tumor biopsies | Both | 19–83 | Open-label, non-randomized dose escalation study to Clinical trial Phase I | Determine if FOLFIRI in combination with flavopiridol presents therapeutic activity | Flavopiridol enhance the effects of FOLFIRI | [25] |
Artepillin | 165 μ mol artepillin C (extract of Propolis)/day 3 months | Japan | 30 patients (15 treatment, 15 placebo) Premetastatic adenomas Biopsies | Both | 40–75 | Randomized, placebo controlled, double-blind trial | Evaluate the effects of artepillin C on colon cancer formation | Not effectiveness in preventing colon cancer. Detrimental side effects on muscle cells | [26] |
Curcuma extract | Capsules at doses between 440 and 2200 mg/day, containing 36–180 mg of curcumin; 4 months. | UK | 15 patients Advanced CRC refractory to chemotherapy Colorectal tissue biopsy | Both | 42–72 | Dose-escalation pilot study | Investigate potential biomarkers of the systemic efficacy of curcumin: GST and M1G | 440 mg of Curcuma extract produced a decrease in lymphocytic GST activity | [27] |
Curcumin | 450, 1800, or 3600 mg of curcumin daily, for 7 days before surgery | UK | 12 patients (7 male, 5 female) No placebo CRC Colorectal tissue biopsy | Both | 47–72 | Dose-scalation study | Test pharmacologically active levels of curcumin measured based on effects on levels of M1G and COX-2 | 3600 mg of curcumin reduced M1G levels. COX-2 protein levels were not affected | [28] |
Curcumin + Quercetin | Curcumin 480 mg and quercetin 20 mg orally 3 times a day 3–6 months | USA | 5 patients (3 men, 2 women) Adenomatous polyposis | Both | 22–54 | Proof-of principle | Evaluate the effect of curcumin and quercetin in familiar adenomatous polyposis | Decrease in polyp number and size after a mean of 6 months of treatment | [29] |
Curcumin | Curcumin capsules 360 mg curcumin, thrice/day during the period ahead of surgery | China | 126 patients Curcumin (37 female and 26 male) Vehicle (34 female 28 male) CRC Biopsy/blood | Both | 34–82 | Randomized controlled trial | Effects of treatment with curcumin on CRC patients | Increased body weight. Decreased serum TNF-α levels. Increased apoptosis of tumor cells and enhanced expression of p53 | [30] |
Curcumin | Pure curcumin (1500 mg orally, twice/day), or placebo, 12 months. | USA | 44 patients (21 treatment, 23 placebo), Familiar adenomatous polyposis | Both | 18–35 | Double-blind, randomized trial | Determine safety and efficacy of curcumin | Few adverse effects No difference in mean number or size of adenomas | [31] |
Curcumin | 2 g oral curcumin daily during chemotherapy | UK | 27 patients (9 FOLFOX, 18 CUFOX (curcumin + FOLFOX)) CRC patient plasma | Not specified | 53–78 | Phase IIa open-labeled randomized controlled trial | Assess safety, efficacy, and CXCL1 in patients receiving CUFOX | Curcumin did not significantly alter CXCL1 over time. Curcumin is a safe and tolerable adjunct to FOLFOX chemotherapy | [32] |
Curcumin + Anthocyanin | Curcumin: 100 mg, 2 times/day Anthocyanin: 500 mg, 2 times/day | Italy | 29 patients (treated: 10 men + 5 women); 14 placebo: 7 + 7) Pre-metastatic adenoma biopsy | Both | Treatment 70.8 placebo 67.9 | Proof-of principle | Evaluate the preventive effect of curcumin combined with anthocyanin | Reduction in NF-κB expression in adenoma tissue. Potentially favorable | [33] |
Curcumin + Anthocyanin | Daily dose of 1 g of curcumin and 1 g of anthocyanin | Italy | 29 patients (15 treatment, 14 placebo), Adenomatous polyp | Both | 18–85 | Randomized, double-blind, placebo-controlled, phase II presurgical trial | Analyze the effects on circulating biomarkers of inflammation and metabolism | No modulation of circulating biomarkers. Increase in IL-6 | [34] |
Curcuminoids | Curcuminoid capsules (500 mg/day), for 8 weeks. | Iran | 64, treated 59, placebo CRC (stage 3) Blood samples | Both | 58–63 | Double-blind placebo-controlled trial | Explore the effects of curcuminoids on pro- and anti-inflammatory cytokines and quality of life in patients undergoing chemotherapy | No improvement in cytokines. Decrease in erythrocyte sedimentation rate and C-reactive protein. Improved quality of life | [35] |
Curcumin | Isolated compound 4 g orally, twice daily during radiotherapy and 6 days after | USA | 22 patients (13 men, 8 treatment + 5 placebo and 9 women, 7 treatment + 2 placebo). Rectal cancer Biopsy/plasma | Both | 28–75 | Phase II randomized double blinded trial | Evaluate the efficacy of curcumin with pre-operative chemoradiation for rectal cancer | No increase in response rates in chemoradiation therapy due to unpredictable bioavailability of curcumin | [36] |
Resveratrol | 8 daily doses of resveratrol at 0.5 or 1.0 g prior to surgical resection | UK | 20 patients (9 male–11 female) CRC Blood/colorectal biopsy | Both | 46–83 | Clinical trial | Analyze the affect of resveratrol on Ki67 expression | Reduction in tumor cell proliferation. Decreased tumor cell Ki-67 staining | [37] |
Resveratrol | SRT501, micronized resveratrol 5.0 g daily for 14 days | UK | 9 Patients (6 treatment, 3 placebo) Stage IV CRC and hepatic Metastases Plasma/hepatic tissue | Both | >18 | Phase I, randomized double-blind clinical trial | Asses the safety, pharmacokinetics, and pharmacodynamics of the formulation | Cleaved caspase-3, a marker of apoptosis, was increased in malignant hepatic tissue | [38] |
Silymarin (4 compounds: silybin, isosilybin, silychristin, silydianin) | Silymarin capsules (150 mg) 3 times/day for 7 days from the beginning of chemotherapy | Taiwan | 70 patients (35 + 35) Metastatic CRC FOLFIRI plus bevacizumab | Both | 20–80 | Prospective open label pilot study | Evaluate the effect of silymarin supplementation reducing the toxicity of chemotherapy | Fewer adverse effects like diarrhea and nausea. No significant differences in hepatic toxicities | [39] |
Isoflavones | 8-week isolated (84 mg/d). isoflavone tablets | Netherlands | 37 patients, 17 intervention 20 placebo Family history of CRC or a personal history of colorectal adenomas | Men | 40–75 | Randomized, placebo-controlled, double-blind | Investigate the effect of an isolated isoflavone supplementation serum concentrations of total IGF-I | No influence on circulating IGF concentrations in men at a high risk of CRC. IGF-I-lowering effect in equol producers only | [40] |
Soy Isoflavones | Soy isoflavones Treatment (83 mg isoflavones Control group (3 mg isoflavones). | USA | 125 Patients Adenomatous colorectal polyps Biopsies colon and rectum | Both | 50–80 | 12-month randomized, double-blinded, placebo-controlled dietary intervention | Test if soy isoflavones decrease epithelial cell proliferación | Soy isoflavones do not reduce colorectal epithelial cell proliferation | [41] |
Isoflavone | 8-week supplementation with red clover-derived isoflavones (84 mg/d) | Netherlands | 34 Patients 15 isoflavone 19 placebo Colorectal adenomas or family history of CRC Plasma/biopsy | Women | 50–75 | Randomized, placebo-controlled, double-blinded, crossover trial | Investigate the effect of isolated isoflavones on IGF system components | No changes in circulating levels of IGF system components or in colorectal tissue mRNA expression | [42] |
Epigallocate chin gallate | Polyphenon E (Poly E, epigallocatechin gallate); 6 months of ora (780 mg EGCG) daily | USA | 39 patients 19 Poly E 20 placebo Rectal ACF (putative precursors of CRC) | Both | >40 | Randomized, double-blinded, and placebo-controlled trial | Study preventive efficacy and safety of Poly E in subjects with rectal ACF | No reduction of rectal ACF number relative to placebo | [43] |
Fisetin | 100 mg capsule of Wax-Tree-derived fisetin/day 7 consecutive weeks | Iran | 37 patients 18 treated, 19 control CRC Stages II-II Blood samples Chemotherapy | Both | 55 | Double-blind, randomized placebo-controlled clinical trial | Assess the efficacy of fisetin supplementation the inflammatory status and MMP levels | Fisetin reduced levels of IL-8 and MMP-7. Act as complementary antitumor agent | [44] |
Flavonoid mixture | Daily dose of 20 mg apigenin and 20 mg epigallocathechin-gallate | Germany | 87 patients, 31 treated 56 control group Resected colon cancer and polypectomy | Both | 69–82 | Controlled clinical trial. Prospective and observational cohort study | Investigate biological prevention with flavonoids the recurrence risk of neoplasia | Sustained long-term treatment could reduce the recurrence rate of colon neoplasia | [45] |
Diet | Intake of the six flavonoid subgroups 4 years | USA | 1905 Patients (control 947; intervention 958) Colorrectal adenomas | Both | 61 | Randomized dietary intervention | Examine the effectiveness of a low-fat, high-fiber, high-fruit, and high-vegetable diet on adenoma recurrence | High intake of flavonols was associated with a decreased risk of advanced adenoma recurrence | [46] |
Diet | Intake of flavonols (quercetin, kaempferol, and myricetin) and flavones (apigenin and luteolin). | USA | 38,408 women, 3234 developed cancer after 11 years of follow-up All kinds of cancers/305 CRC | Women | >45 | Prospective study | Investigate the association between the intake of selected flavonoids and risk of cancers | There was no association between intake of flavonoid-rich foods and the incidence of cancers. No prevention | [47] |
Diet | Low-fat, high-fiber, high-fruit and vegetable, diet Flavonols isorhamnetin, kaempferol, and quercetin | USA | 872 participants Histologically confirmed colorectal adenomas Blood | Both | >35 | Polyp Prevention Trial 4-year | Examine the effectiveness of a low-fat, high-fiber, high-fruit, and vegetable diet on adenoma recurrence | High flavonol intakes decrease IL-6 concentrations. Reduction of the risk of adenoma recurrence | [48] |
Diet | Intake of lignan and proanthocyanidin | USA | 1859 patients control 930; intervention 929 Presence of adenomas | Both | 55 | Randomized, nutritional intervention trial | Evaluate if consumption of a high-fiber, high-fruit, high-vegetable, and low-fat diet would decrease the risk of adenoma recurrence | High lignan intake may increase the risk of adenoma recurrence in women | [49] |
Diet | MB-6 6 capsules of 320 mg each, 3 times/day | Taiwan | 60 patients 29 treated 31 placebo CRC Follow-up assessment 77 weeks | Both | 63 | Proof-of-concept clinical study 77 weeks of follow-up | Test if MB-6 would increase the effectiveness of chemotherapy (FOLFOX) | MB-6 group had a lower disease progression rate and presented less adverse events and a decreased serum creatinine | [50] |
Diet | Flavonoid subclasses (flavonols, flavones, flavanones, flavan-3-ols, and anthocyanins) 26 years | USA | 42,478 male and 76,364 female 2519 CRC cases (1061 men, 1458 women) Evaluation of cancer risk | Both | 30–75 | Polyp Prevention Trial | Examine if higher dietary intakes of flavonoids was associated with a lower risk of CRC | Higher dietary intakes of flavonoids was not associated with a lower risk of CRC. | [4] |
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López-Gómez, L.; Uranga, J.A. Polyphenols in the Prevention and Treatment of Colorectal Cancer: A Systematic Review of Clinical Evidence. Nutrients 2024, 16, 2735. https://doi.org/10.3390/nu16162735
López-Gómez L, Uranga JA. Polyphenols in the Prevention and Treatment of Colorectal Cancer: A Systematic Review of Clinical Evidence. Nutrients. 2024; 16(16):2735. https://doi.org/10.3390/nu16162735
Chicago/Turabian StyleLópez-Gómez, Laura, and Jose Antonio Uranga. 2024. "Polyphenols in the Prevention and Treatment of Colorectal Cancer: A Systematic Review of Clinical Evidence" Nutrients 16, no. 16: 2735. https://doi.org/10.3390/nu16162735
APA StyleLópez-Gómez, L., & Uranga, J. A. (2024). Polyphenols in the Prevention and Treatment of Colorectal Cancer: A Systematic Review of Clinical Evidence. Nutrients, 16(16), 2735. https://doi.org/10.3390/nu16162735